Synthetic Modeling of Copper Protein Active Sites

描述(申请人提供)：铜在许多重要的环境和生物过程中起着关键作用，特别是当铜被包裹在广泛分布于自然界的酶中时。酶活性部位的铜离子具有多种重要功能，包括结合和激活氧气(O2)以实现代谢上重要的化学反应，以及在微生物呼吸过程中还原氧化性含氮化合物，如亚硝酸盐和一氧化二氮(N2O)，这些过程在全球氮循环中至关重要。尽管进行了广泛的研究，但有关这些过程的详细分子水平途径的许多问题仍然没有得到回答。这里描述的研究通过综合建模方法解决了这些问题中的一些。在这种方法中，设计的复制铜酶活性中心结构和功能的低分子量络合物被表征，并研究它们的反应性。目标是详细了解与生物系统相关的几何结构、电子结构、成键和反应机制。特别是，这项研究的目的是详细了解参与O2和N2O结合和激活的一组重要的含铜酶的功能的基本化学基础。这一目标将通过三个具体目标来实现：(1)单铜中心的氧气活化，(2)多铜中心的氧气活化，以及(3)用于模拟一氧化二氮还原酶CUZ位点的铜硫化学。在AIMS(1)和(2)中，将制备高活性的单铜和多铜氧化物种的合成类似物，以评估它们在结合和激活O2的酶中的可能作用。在目标(3)中，将合成在环境重要的酶-一氧化二氮还原酶中发现的不寻常的四铜硫化物簇(CUZ)的新的多铜(I)-硫化物模型，并将研究它们与N2O的反应活性。除了渴望深入了解铜酶的结构/功能关系外，拟议的工作还旨在开发具有基础意义的新型铜化学。与公众健康相关：这项研究旨在详细了解参与O2和N2O结合和激活的一组重要的含铜酶功能的基本化学基础。氧气激活酶参与了生命中许多重要的生物学过程，包括呼吸作用、金属离子稳态(其破坏会导致疾病)，以及对人类健康至关重要的重要有机代谢物、激素和神经递质的产生。微生物酶一氧化二氮还原酶对N2O的还原将温室气体转化为惰性氮气，这一过程被认为是全球氮循环的关键组成部分，因此与公众健康直接相关。

DESCRIPTION (provided by applicant): Copper plays a key role in numerous environmentally and biologically important processes, particularly when encapsulated within enzymes that are widely distributed in Nature. The copper ions in the active sites of enzymes perform a variety of significant functions, including the binding and activation of dioxygen (O2) for effecting metabolically significant chemical reactions and the reduction of oxidized nitrogen-containing compounds like nitrite and nitrous oxide (N2O) during microbial respiratory processes important within the global nitrogen cycle. Despite extensive research, many questions remain unanswered concerning the detailed molecular level pathways of these processes. The research described herein addresses some of these questions through the synthetic modeling approach. In this approach, low molecular weight complexes designed to replicate aspects of copper enzyme active site structure and function are characterized and their reactivity studied. The goals are to develop detailed understanding of geometries, electronic structures, bonding, and reaction mechanisms relevant to the biological systems. In particular, the research aims to provide detailed understanding of the fundamental chemistry underlying the function of an important subset of copper-containing enzymes involved in the binding and activation of O2 and N2O. This objective will be addressed through three specific aims: (1) Dioxygen Activation at Monocopper Sites, (2) Dioxygen Activation at Multicopper Sites, and (3) Copper-Sulfur Chemistry for Modeling the CuZ Site of Nitrous Oxide Reductase. In aims (1) and (2), synthetic analogs of highly reactive mono- and multicopper oxidizing species will be prepared in order to evaluate their possible role in enzymes that bind and activate O2. In aim (3), new multicopper(I)-sulfide models of the unusual tetracopper-sulfide cluster (CuZ) found in an environmentally important enzyme, nitrous oxide reductase, will be synthesized and their reactivity with N2O will be studied. In addition to aspiring to a deep understanding of copper enzyme structure/function relationships, the proposed work is aimed at developing novel copper chemistry of fundamental significance. PUBLIC HEALTH RELEVANCE: The research aims to provide detailed understanding of the fundamental chemistry underlying the function of an important subset of copper-containing enzymes involved in the binding and activation of O2 and N2O. The dioxygen-activating enzymes are involved in a plethora of important biological processes central to life, including respiration, metal ion homeostasis (the disruption of which causes disease), and the production of important organic metabolites, hormones, and neurotransmitters essential to human health. The reduction of N2O by the microbial enzyme nitrous oxide reductase converts this greenhouse gas to inert N2 in a process recognized to be a critical component of the global nitrogen cycle and thus directly relevant to public health.